Currently, a large variety of physiologically active peptides or physiologically active protein preparations, such as insulin, growth hormone, atrial natriuretic peptide, calcitonin, LH-RH derivatives, parathyroid hormone and adrenocorticotropic hormone derivatives, are being marketed as pharmaceutical agents. However, because these physiologically active peptides and physiologically active proteins are inactivated by the degrading activity of proteases in the gastrointestinal tract, they cannot be easily developed as oral formulations and almost all of them are prepared in the form of parenteral formulations, mainly for injection. The administration of an injection, however, requires a hospital visit by the patient and is also painful, and therefore parenteral transmucosal formulations are desired that allow painless administration to be performed at home.
Nasal administration is one such parenteral transmucosal administration route. Here, the target is the mucous membrane of the nasal cavity, which has a structure with a developed vasoganglion, mucous membranes of the superior nasal concha, medial nasal concha and inferior nasal concha, and a wide surface area, and therefore nasal administration is expected to allow higher absorption of drugs compared to the oral, rectal and pulmonary mucous membranes. However, absorption of a peptide drug through the nasal mucosa is impeded by numerous obstacles such as low permeability through mucous membranes and degradation of physiologically active peptides by mucosal enzymes, while the bioavailability (BA), which is an index of the degree of migration of a substance into the blood, is by no means satisfactory. A variety of modifications have therefore been proposed for nasal formulations to increase absorption of peptides by nasal administration.
Conventional methods for increasing absorption of physiologically active peptides by nasal administration include 1) methods in which a substance that promotes absorption of physiologically active peptides through the nasal mucosa is added to or compounded with the composition to be administered, 2) methods in which a substance that inhibits degradation of physiologically active peptides on the nasal mucosa is added to or compounded with the composition, and 3) methods in which the residence time of the bioactive substance in the nasal mucosa is extended to increase absorption of the physiologically active peptides.
1) As regards methods in which a substance that promotes absorption of physiologically active peptides through the nasal mucosa is added to or compounded with the composition, a mucolytic agent is often used as a mucous membrane absorption accelerator. WO2004/078211 discloses a nasal administration powder formulation with improved absorption, by addition or compounding of a bioactive substance such as a cytokine, peptide hormone or growth factor, with a non-water-absorbing and poorly water-soluble cellulose derivative (such as ethylcellulose, cellulose acetate or nitrocellulose) as the base, and a mucolytic agent which might be a cysteine derivative such as N-acetyl-L-cysteine or an active SH group-containing alcohol. According to the invention described therein, when the nasal administration formulation is atomized and inhaled intranasally, the presence of the non-water-absorbing and poorly water-soluble substance serving as the base causes the physiologically active peptide and mucolytic agent to adhere and reside on the nasal mucosa, dissolving into the mucus in a trace amount, thus producing a locally high concentration solution of the physiologically active peptide and mucus solubilizer. Since it has been reported that one of the actions of N-acetyl-L-cysteine is to cleave disulfide bonds of mucus mucopolysaccharides (Non-PTL 1), the aforementioned invention takes advantage of efficient diffusion of the drug by rapid liquefaction of the mucus layer by N-acetyl-L-cysteine, as the mucolytic agent, but does not disclose any effect of the cellulose acetate, as the base, on absorption or BA of the drug.
2) As regards formulations with addition or compounding of an inhibitor of physiologically active peptide degradation, some methods involve addition or compounding of inhibitors against proteases that are present in the nasal mucosa. In Japanese Unexamined Patent Publication (kokai) No. 7-206699, there are disclosed peptide nasal and protein nasal formulations with compounding of gabexate mesylate or nafamostat mesylate, which have serine protease inhibiting activity, and it teaches that the BA is improved in these formulations.
However, safety is an issue in the methods of adding or compounding a mucolytic agent according to the solution means of 1) and the methods of adding or compounding a substance with protease inhibiting activity according to the solution means of 2), because of reported irritation of the nasal mucosa by the added or compounded substances, and therefore nasal formulation compositions are desired that are safer while exhibiting high BA for physiologically active peptides.
In methods that extend the residence time on the nasal mucosa, as according to 3), selection of the base is the most important factor. In the prior art, bases are often added that increase viscosity for greater adhesion of physiologically active peptides to the mucous membrane. Japanese Examined Patent Publication (kokoku) No. 62-42888, for example, describes a powdered composition for nasal administration that comprises a physiologically active polypeptide and a water-absorbing and water-insoluble base such as crystalline cellulose, α-cellulose or crosslinked sodium carboxymethylcellulose. A water-absorbing and water-insoluble base, when used for intranasal administration, absorbs water of the nasal mucosa and transforms the particles into a viscous liquid state such that they moderately disperse without flowing, thereby allowing the particles to reside in the adhering sections of the nasal mucosa so that the high molecular weight polypeptides satisfactorily contact the nasal mucosa, whereby absorption of the polypeptides is increased.
Japanese Unexamined Patent Publication (kokai) 10-59841 discloses using a specified amount of a water-absorbing gel-forming base such as hydroxypropylcellulose or hydroxymethylcellulose in combination with a physiologically active peptide and a water-absorbing and water-insoluble base such as crystalline cellulose, the particle sizes of the bases being 10 to 350 microns for the water-absorbing and water-insoluble base and 10 to 100 microns for the water-absorbing gel-forming base, so that the physiologically active peptide is widely dispersed throughout the nasal cavity when administered intranasally, and the gel-forming base gels and resides in the nasal cavity, resulting in an increased maximum blood concentration of the drug.
According to this prior art, the preferred bases that exhibit high BA for physiologically active peptides are water-absorbing and water-insoluble cellulose derivatives, and especially crystalline cellulose. However, water-absorbing and water-insoluble bases can produce unpleasant feelings such as itchiness in the nasal cavity, because they absorb water of the mucous membrane after atomized in the nasal cavity, and therefore the nasal formulation has been problematic in terms of compliance.